JP4249012B2 - Novel 2H-pyridazin-3-one derivative, pharmaceutical composition containing the derivative, and process for producing this active ingredient - Google Patents

Description

  The present invention relates to a novel 2H-pyridazin-3-one derivative, a pharmaceutical composition containing the derivative as an active ingredient, and a method for producing the active ingredient. This novel compound has a neuroleptic action and is mainly used for the treatment of schizophrenia.

Psychiatric disorders (schizophrenia, anxiety, depression), including various clinical aspects of emotions, form a major challenge for medicine. About 1% of the population suffers from schizophrenia. However, recent drug therapies are not always completely suitable for the treatment of such diseases. Clinically, schizophrenia is characterized by two fundamentally different syndromes with respect to etiology and response to drug therapy. These are so-called positive or productive symptoms (hall hallucinations, delusions) and negative or deficient symptoms (loss of emotional vitality, speechlessness) (Crow, TJ, Brit. Med. J., 280 , 66 (1980)). The formation of productive symptoms is due to hyperfunction of the mesolimbic dopaminergic system (Kahn, RS and Davis, KL, The Fourth Reneration of Progress, Editor: Bloom, FE and kupfer, DJ, Raves Press, New York , p1215 (1995)), these symptoms are well controlled by so-called classic neuroleptics (haloperidol, chlorpromazine). However, in the case of a negative symptom, it is characterized by decreased function of the mesolimbic dopaminergic system (Knable, MB and Winberger, DM, Psychopharmacology, 11 , 123 (1997)), and the above drugs are ineffective, In addition, they can cause worsening of negative symptoms. So-called classic neuroleptics (haloperidol, chlorpromazine), which are primarily dopamine D ₂ receptor antagonists, have been the center of therapy to date. As a result, as described above, they have many undesirable side effects and are ineffective in one of the schizophrenic syndromes (negative symptoms) (Ellenbroek, BA, Pharmacol. Ther., 57 , 1 ( 1993)).

Following the discovery of 5-HT _2A receptors (Leysen et al., Biochem. Pharmacol., 27 , 307 (1978)), the role of these receptors has been evaluated in therapeutic effects against schizophrenia. Clozapine is the first drug that binds more strongly to the 5-HT _2A receptor than the D ₂ receptor and does not have the undesirable side effects that are characteristic of classic drugs, and clozapine also controls negative symptoms ( Melzer, HY, Schizophr. Bull., 17 , 263 (1991)). Following clozapine, several new next-generation neuroleptics (eg, olanzapine, seroquel, etc.) have been developed, which are recognized as standard atypical neuroleptics. The above-mentioned new atypical drugs are equally effective for the positive symptoms (hall hallucinations and delusions) and negative symptoms (emotional emptying, speechlessness) that are characteristic of schizophrenia.

A 3- (1-substituted-4-piperidinyl) -1,2-benzisoxazole derivative having a nerve blocking action is disclosed in a paper (J. Med. Chem., 28 (6), 761-769 (1985)). Has been. 3 (2H) -pyridazinenone derivatives with antiarrhythmic activity are known from US Pat. No. 5,395,934.

  The goal of the present invention is a novel compound having a neuroleptic action that has a favorable effect on both symptoms of schizophrenia, is more effective than clozapine, and does not have any side effects of extrapyramidal or endocrine systems Is to prepare.

（式中、Ｒは、水素又はＣ_1-4アルキル基であり；Ｘ及びＹは、独立して、水素原子、ハロゲン原子又は式(II)

（ここで、ｎは１又は２である）で表される基であり、ただし、Ｘ及びＹの１つは、常に式(II)で表される基であり、他の１つは、水素原子又はハロゲン原子である）で表される新規な2H-ピリダジン-3-オン誘導体及びその薬学上好適な酸付加塩に関する。 More specifically, the present invention provides compounds of formula (I)

Wherein R is hydrogen or a C _1-4 alkyl group; X and Y are independently a hydrogen atom, halogen atom or formula (II)

(Where n is 1 or 2), provided that one of X and Y is always a group represented by the formula (II), and the other is hydrogen. A 2H-pyridazin-3-one derivative represented by formula (1) or a pharmaceutically suitable acid addition salt thereof.

  The inventors have found that a 2H-pyridazin-3-one derivative substituted with a (6-fluoro-1,2-benzisoxazol-3-yl) piperidin-1-ylalkylamino group has a very favorable nerve blocking action. And obtained knowledge that it can be used to treat both symptoms of schizophrenia.

In the specification and claims, a C _1-4 alkyl group is a methyl group, an ethyl group, an isopropyl group, an n-propyl group, an n-butyl group, a secondary butyl group, an isobutyl group or a tertiary butyl group. Yes, preferably a methyl group.

  The halogen atom is a fluorine, chlorine, bromine or iodine atom, preferably a chlorine atom.

  Pharmaceutically suitable acid addition salts of 2H-pyridazin-3-one derivatives represented by formula (I) are inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., or formic acid, acetic acid, maleic acid Means non-toxic acid addition salts of the derivatives formed by organic acids such as fumaric acid, lactic acid, tartaric acid, succinic acid, citric acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and the like.

  A preferred subgroup of the compounds of the present invention is that in formula (I), X is a group represented by formula (II); Y is a hydrogen atom or a halogen atom; R and n in formula (I) It consists of 2H-pyridazin-3-one derivatives of formula (I) and their pharmaceutically suitable acid addition salts, which are related and limited.

  In the above subgroup, particularly preferred 2H-pyridazin-3-one derivatives represented by formula (I) and pharmaceutically suitable acid addition salts thereof are those in which Y represents a hydrogen atom or a chlorine atom in formula (I). , R means a hydrogen atom or a methyl group, and X is a group represented by the formula (II) (where n is defined in relation to the formula (I)).

  Another preferred subgroup of the compounds of the invention is that in formula (I), Y is a group represented by formula (II); X is a hydrogen atom or a halogen atom; and R and n are compounds of formula (I 2H-pyridazin-3-one derivatives of formula (I) and their pharmaceutically suitable acid addition salts, which are limited in relation to

  In this subgroup, particularly preferred 2H-pyridazin-3-one derivatives of formula (I) and their pharmaceutically suitable acid addition salts are those of formula (I) wherein X represents a chlorine atom and R is Means a methyl group, wherein Y is a group represented by formula (II), wherein n is defined in relation to formula (I).

Among the above particularly preferred compounds, the following are preferred:
4-chloro-5- {2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] ethylamino} -2-methyl-2H-pyridazin-3-one ,
4-chloro-5- {3- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] propylamino} -2-methyl-2H-pyridazin-3-one And pharmaceutically suitable acid addition salts thereof.

（式中、Ｚは脱離基であり；Ｒ、Ｙ及びｎは前記のとおりである）で表されるアルキルアミノピリダジン-3-オン誘導体を、式(IV)

で表される6-フルオロ-3-ピペリジン-4-イル-1,2-ベンゾイソオキサゾールと反応させるか；又は
ｂ）式(Ｉ)において、Ｘが式(II)で表される基であり、Ｙ、Ｒ及びｎが式(Ｉ)に関連して定義されるものである式(Ｉ)で表される2H-ピリダジン-3-オン誘導体を調製するため、式(Ｖ)

（式中、Ｚは脱離基であり；Ｒ、Ｙ及びｎは前記のとおりである）で表されるアルキルアミノピリダジン-3-オン誘導体を、式(IV)で表される6-フルオロ-3-ピペリジン-4-イル-1,2-ベンゾイソオキサゾールと反応させるか；又は
ｃ）式(Ｉ)において、Ｘが水素原子を表し、Ｙが式(II)で表される基であり、及び／又はＹが水素原子を表し、Ｘが式(II)で表される基であり、Ｒ及びｎが式(Ｉ)に関連して限定されるものである式(Ｉ)で表される2H-ピリダジン-3-オン誘導体を調製するため、式(VI)

（式中、Ｘ'及びＹ'はハロゲン原子を意味し；Ｒは前記のとおりである）で表されるジハロピリダジン-3-オン誘導体を、式(VII)

（ここで、ｎは前記のとおりである）で表されるベンゾイソオキサゾール誘導体と反応させ；及び
所望により、得られた式(Ｉ)で表される2H-ピリダジン-3-オン誘導体を、その薬学上好適な酸付加塩に変換するか、又はその酸付加塩から脱離させる。 The compounds of the present invention are prepared as follows.
a) In formula (I), Y is a group represented by formula (II) and X, R and n are represented by formula (I) as defined in relation to formula (I) To prepare 2H-pyridazin-3-one derivatives, the compound of formula (III)

(Wherein Z is a leaving group; R, Y and n are as defined above), an alkylaminopyridazin-3-one derivative represented by the formula (IV)

Or b) in the formula (I), X is a group represented by the formula (II), or 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole represented by In order to prepare 2H-pyridazin-3-one derivatives of formula (I), wherein Y, R and n are as defined in relation to formula (I)

(Wherein Z is a leaving group; R, Y and n are as defined above), an alkylaminopyridazin-3-one derivative represented by the formula (IV) Reacting with 3-piperidin-4-yl-1,2-benzisoxazole; or c) In formula (I), X represents a hydrogen atom and Y is a group represented by formula (II); And / or Y represents a hydrogen atom, X is a group represented by formula (II), and R and n are represented by formula (I) as defined in relation to formula (I) To prepare 2H-pyridazin-3-one derivatives, the compound of formula (VI)

(Wherein X ′ and Y ′ represent a halogen atom; R is as defined above), a dihalopyridazin-3-one derivative represented by the formula (VII)

(Wherein n is as defined above); and, if desired, the obtained 2H-pyridazin-3-one derivative represented by the formula (I) Conversion to or elimination from a pharmaceutically suitable acid addition salt.

  Processes a), b) and c) of the present invention are methods known from the literature (eg March, J .: Advanced Organic Chemistry, Reactions, Mechanism and Structure, 4th edition, John Wiley & Sons, New York, 1992). Is carried out according to In the case of the process c) of the present invention, depending on the raw material compound, usually a compound of the formula (I) type, that is, in the formula (I), X is a group represented by the formula (II), and Y is a halogen atom A compound, and in formula (I), X is a halogen atom, Y is a group represented by formula (II), and R and n are defined in relation to formula (I) A mixture of compounds is produced. The components of the mixture are separated by conventional methods of preparative organic chemistry, such as fractional crystallization.

  The 2H-pyridazin-3-one derivative of formula (I) can be reacted with an inorganic or organic acid in a manner known per se to obtain its pharmaceutically suitable acid addition salt, or The acid addition salt is eliminated using a suitable inorganic or organic base.

The alkylaminopyridazin-3-one derivatives represented by the formulas (III) and (V) used as raw materials are prepared by the method disclosed in the international patent application (PCT / HU98 / 00054).
6-Fluoro-3-piperidin-4-yl-1,2-benzisoxazole represented by the formula (IV) is a paper (J. Med. Chem., 28 (6), 761-769 (1985)). Is disclosed.

Dihalopyridazin-3-one derivatives represented by the formula (VI) are also known (J. Chem. Soc., 1948 , 2192, 2194).

The benzisoxazole derivative represented by the formula (VII) is described in literature (Arch. Pharm., 329 (1), 3-10 (1996); J. Med. Chem., 28 (12), 1934-1943 (1985). )) From 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole of formula (IV) by aminoalkylation in a known manner.

  The pharmacological activity of the 2H-pyridazin-3-one derivative represented by the formula (I) was examined in the following test.

1. Methods for Modeling Positive Symptoms 1.1 Inhibition of Conditional Avoidance Response (CAR) Antipsychotic (nerve blockage) activity was assessed by measuring the inhibition of learning condition avoidance reflexes. At the start of teaching, male Wistar rats weighing 120-150 g were used in the experiments. The experimental apparatus is a so-called shuttle box consisting of two chambers (size: 24 cm × 24.5 cm × 23 cm) separated from each other by walls. The two chambers were connected by a gate (size: 6 cm × 9 cm). During the test, the animal's task is to move from one room to the other through the gate and avoid punitive (unconditional) stimuli when there is an appropriate warning stimulus . Warning (condition) stimuli appear in the room where the animal stays. Conditional stimulus (CS) is light emission of white light (1 Hz) for 15 seconds. An unconditional stimulus (US) is a random electric shock to the sole of 0.6 mA strength that appears in the last 5 seconds of a conditioned stimulus. Passing from one chamber of the shuttle box to another in the conditioned stimulus was considered an avoidance response, while passing during an unconditional stimulus was considered an escape response. When both reactions occurred, the actual stimulation was stopped and the study was terminated. The intertrial interval (ITI) is 15 seconds. 80 trials were performed per day. Learning ability was measured as a ratio (%) of the number of successful avoidance responses / total number of trials. The effects of neuroleptics were measured on animals that showed at least 75% capacity after stabilization of the conditioned reflex. Test compounds were administered to the rats once a week, 1 hour prior to the series of experiments. When evaluating the effects of neuroleptics in each group, the animal's ability on the previous day was used as a control. From the data obtained, a 50% inhibitory dose (ID ₅₀ ) was determined. These values are shown in Table 1. As control substances, chlorpromazine (2-chloro-10- (3-dimethylaminopropyl) phenothiazine) and clozapine (8-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo [b, e] [1 , 4] diazepine).

Table 1
Preventing condition avoidance reactions

Compound (Example No.) Conditional reflection, ID ₅₀ (mg / kg)
1 0.7
2 5.8
4 0.3-0.5
5 ≦ 3.0
Chlorpromazine 13.2
Clozapine 21.3

  The results shown in Table 1 have been tested to show that each compound of the present invention effectively prevented the condition avoidance reaction. Its potency is at least an order of magnitude higher than that of the control molecule.

1.2 Inhibition of apomorphine stereosis and climbing on mice In experiments, male NMRI mice weighing 20-24 g were used. The animals are each treated with a carrier and test substance (20 ml (volume) / kg (body weight)) and after 30 minutes the animals can be covered with Pyrex® glass for habituation. (Size: 12 cm × 12 cm × 12 cm). After 30 minutes, apomorphine hydrochloride 1 ml / kg was administered subcutaneously to the animals in a volume of 10 ml / kg. Measurement of anabolic behavior was started immediately after treatment with apomorphine and continued for 25 minutes. The measurement was carried out by means of a scale with 5 grades. The five grades are as follows.
0 points: normal behavior equivalent to that of the control animal 1 point: persistent exploration activity; sniffing or occasionally moving the head sideways 2 points: intense, continuous movement of the head or sniffing Action; Regular exploration activity 3 points: Occasional licking, biting or biting behavior; Behavior of alternating sniffing or moving the head; spontaneous movement in a very short time 4 points: no spontaneous movement or exploration Continually violently licking and / or biting at the same location without any activity

  Climbing was considered as the condition when the mouse climbed to the vertical wall with at least three limbs. Evaluation was performed in the last 10 minutes, based on yes / no (+/-).

Assessment of stereotypy: Each animal was recorded, taking into account the highest point obtained during observation. From the maximum point value, an average value for each group was calculated, and this average value was related to the average value of the control group to calculate the effect in%. From these values, the ID ₅₀ (dose that produced 50% inhibition) was calculated by linear regression based on the dose-response relationship.

Climbing assessment: When assessing the inhibitory effect, the number of animals that showed climbing was considered. The frequency in each group was calculated and the results obtained for the control group were taken as 100% and the effect was measured as%. From the effect (%), the value of ED ₅₀ (dose that produces inhibition in 50% of the animals) is determined according to Litchfield and Wilcoxon (J. Pharmacol. Exp. Ther., 96 , 99 (1949)). Calculated based on

  The results obtained are summarized in Table 2. Again, chlorpromazine and clozapine were used as control substances.

Table 2
Prevention of apomorphine-induced stereotypy and climbing

Compound (Example No.) Prevention of stereotypy, ID ₅₀ (mg / kg) Blocking climbing, ED ₅₀ (mg / kg)
1 0.4 0.3
2 2.0 0.6
3 1.2 0.8
4 0.2 0.06
5 2.0 0.6
Chlorpromazine 6.8 6.1
Clozapine 35.4 11.8

  From the data in Table 2, it is understood that the compounds of the invention antagonize the behavioral response elicited by apomorphine at a dose somewhat lower than that of the control substance. Similar to atypical clozapine, the new compounds tested blocked the climbing response more effectively than for stereotypy.

2. Test to model negative symptoms 2.1 Prevention of hyperkinetic movements caused by phencyclidine (PCP) Using one animal per aisle, a 10-channel “digital exercise measuring device” The experiment was conducted. At each measurement site (box of size 44 cm × 8 cm × 10 cm), the movement of the animals was indicated by blocking (recorded by the instrument) three parallel infrared light beams. At 60 minutes after oral administration (20 ml / kg) of the compound and carrier to be tested, each animal received phencyclidine (1- (1-phenylcyclohexyl) piperidine) 3 mg / kg at a dose of 10 ml / kg. It was administered intraperitoneally. After 15 minutes, the treated animals were placed in the apparatus, and after 45 minutes, the number of infrared light blocking in each passage was read. Ten mice were used as each test group. During the evaluation, the average value was calculated in each test group, and the effect was determined with the average value in the control group as 100%. From the effect (%), the value of ID ₅₀ was calculated by linear regression based on the dose-effect relationship. The obtained results are shown in Table 3. As control substances haloperidol (4- (4-chlorophenyl-4-hydroxy-1-piperidinyl) -1- (4-fluorophenyl) -1-butanone) and clozapine were used.

Table 3
Prevention of hyperactivity induced by phencyclidine

Compound (Example No.) ID ₅₀ (mg / kg)
1 0.4
4 0.07
5 0.46
6 0.9
7 0.4
8 0.2
9 1.4
Haloperidol 1.2
Clozapine 2.9

  From Table 3, it can be seen that the tested compounds of the present invention prevented the increase in behavior induced by phencyclidine more effectively than the control substance.

3. cataleptogenous action
The cataleptogenous action was examined according to the method of Morpurgo (Morpurgo, C., Arch. Int. Pharmacodyn., 137 , 84 (1962)). In the experiment, male Wistar rats weighing 220-240 g were used. One by one, the rat's forelimbs were placed on rubber stoppers and observed how the animals could withstand abnormal postures. Normal (non-catalepsy) animals take their feet off the stopper for a measurement time of 10 seconds. This stiff state with myotonia is assessed as catalepsy if the animal keeps the paw on the stopper for this measurement time. For each compound tested, the minimum effective dose (MED) was determined. Table 4 shows the obtained results. As control substances, haloperidol and risperidone (3- {2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidinyl] ethyl} -6,7,8,9-tetrahydro-2- Methyl-4H-pyrido [1,2-a] pyrimidin-4-one) was used. Also shown in Table 4 is the ratio of ID ₅₀ values characterizing the inhibition of catalepsy-induced dose and conditioned avoidance response (CAR).

Table 4
cataleptogenous action

Compound (Example No.) MED ₅₀ (mg / kg) po ratio Cat / CAR (MED / ID ₅₀ )
4 3 About 6
5 10> 3
6> 30
7-30
8-10
9> 10
Haloperidol 1 1.6
Risperidone 1 2

  From the data in Table 4, it is clear that the compounds of the invention elicit catalepsy in a clearly higher dose range than the control substance (the difference is at least 3 times). From a comparison of the therapeutic dose range and the dose that elicits catalepsy, it is clear that the compound of formula (I) has a significantly advantageous side effect profile over the control substance.

4). Cardiotoxic effects Cardiotoxic effects were measured in vitro in rabbit isolated right ventricular papillary muscles.

Method
A modification of Hacket et al. Was used (Hacket, AM, Mc Donald SJ, P., Schweingruber, F. and Gartwaite, SM: A simple in vitro method to characterize antiarrhythmic drugs, J. Pharmacol. Methods, 23, 107-116. , 1990).

Effective refractory period (ERP) was measured in vitro in rabbit isolated right ventricular papillary muscles.
The contraction of papillary muscle preparations from New Zealand rabbits weighing 2.5-3.2 kg was evaluated. Contractions (same pace at 1 Hz) were recorded by a 4-channel Hugo Sachs device. The effect of the test compound or control was measured at a concentration of 1 μM.

  If a compound clearly prolonged EPR (p <0.01 or p <0.001), the effect was considered cardiotoxic.

  The results are summarized in Table 5.

Table 5

Compound (Example No.) Change in ERP (1 μM) (%)
4 11.1 ± 1.7
5 5.3 ± 0.4
6 6.1 ± 1.9
8 1.5 ± 1.5
9 0.4 ± 1.1
Risperidone 34.8 ± 4.8 ***
Iloperidone 31.9 ± 7.8 **

Note **: p <0.01; ***: p <0.001 vs. baseline

  Surprisingly, the compounds of the present invention have no cardiotoxic effects at a concentration of 1 μM, despite the fact that they contain a benzisoxazole structural moiety. The structurally similar controls risperidone and iloperidone showed considerable and significant cardiotoxicity.

In summary, it can be said that the compounds of the present invention are effective in the treatment of diseases involving mental and emotional disorders. The new compounds have significant therapeutic efficacy against both positive and negative symptoms of schizophrenia. This is supported by the results obtained in tests that measure conditioned avoidance reactions, the inhibition of the action of phencyclidine, as well as in interaction tests triggered by apomorphine. That is, phencyclidine can cause psychotic symptoms in humans that are very similar to the deficient symptoms of schizophrenia. Therefore, the PCP model used in the test is particularly suitable for assessing effects on negative symptoms (Steinpreis, RE, Behav. Brain Res., 74 , 1-2, 45 (1995)). It is particularly striking that the new compounds tested block the climbing response elicited by apomorphine in a dose range that is considerably lower than the stereotypic behavior. According to literature data, the prevention of apomorphine stereosis is associated with the blockade of the linear dopamine receptor, while the prevention of climbing is associated with the blockage of the dopamine receptor in the nucleus accumbens (Costall et al. , Eur. J. Pharmacol., 50 , 39 (1978)), such knowledge is important. As a result, the compounds of the present invention are not expected to cause extrapyramidal side effects at therapeutic doses.

  It has been found that the compounds of the present invention have no cardiotoxic action despite the structural elements of benzisoxazole.

  Based on the above tests, the compounds of the present invention and their pharmaceutically suitable acid addition salts are used as active ingredients in pharmaceutical compositions.

  Furthermore, the present invention relates to a pharmaceutical composition comprising a 2H-pyridazin-3-one derivative represented by the formula (I) or a pharmaceutically suitable acid addition salt thereof and one or more general carriers.

  The pharmaceutical composition of the present invention generally contains 0.1 to 95% by mass of the active ingredient, preferably 1 to 50% by mass, and preferably 5 to 30% by mass.

  The pharmaceutical composition of the present invention is suitable for oral, parenteral, rectal or transdermal administration or topical administration, and is solid or liquid.

  Solid pharmaceutical compositions suitable for oral administration are powders, capsules, tablets, film-coated tablets, microcapsules, etc., and binders such as gelatin, sorbitol, polyvinylpyrrolidone, etc .; excipients such as lactose, glucose, starch, calcium phosphate, etc. Agents; tableting aids such as magnesium stearate, talc, polyethylene glycol, silica, etc .; wetting agents such as sodium lauryl sulfate can be included as carriers.

  Liquid pharmaceutical compositions suitable for oral administration are solutions, suspensions or emulsions, for example, suspending agents such as gelatin, carboxymethylcellulose, etc .; emulsifiers such as sorbitan monooleate; water, oil, glycerin, propylene Solvents such as glycol, ethanol, etc .; preservatives such as methyl p-hydroxybenzoate can be included as carriers.

  Pharmaceutical compositions suitable for parenteral administration generally consist of a bactericidal solution of the active ingredient.

  The above dosage forms and other dosage forms are known per se (see, for example, Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA (1990)).

  A pharmaceutical composition generally contains a dosage unit. A typical dose for an adult patient is 0.1 to 1000 mg of a compound represented by formula (I) or a pharmaceutically suitable acid addition salt thereof per kg body weight per day. The daily dose is administered once or in several divided doses. The actual dose depends on a number of factors and is determined by the physician.

  A pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically suitable acid addition salt thereof mixed with one or more carriers, and the resulting mixture is converted into a pharmaceutical composition in a manner known per se. To be prepared. The methods that can be used are known from the literature, for example Remington's Pharmaceutical Sciences mentioned above.

  One subgroup of the pharmaceutical composition of the present invention contains, as an active ingredient, in formula (I), X is a group represented by formula (II); Y is a hydrogen atom or a halogen atom; R and n Containing a 2H-pyridazin-3-one derivative of formula (I) or a pharmaceutically suitable acid addition salt thereof, as defined in relation to formula (I).

  In this subgroup, a suitable pharmaceutical composition contains, as an active ingredient, in formula (I), R represents a hydrogen atom or a methyl group, Y represents a hydrogen atom or a chlorine atom, and X and n are as defined above. Or a 2H-pyridazin-3-one derivative represented by the formula (I) or a pharmaceutically suitable acid addition salt thereof.

  Another subgroup of the pharmaceutical composition of the present invention contains, as an active ingredient, in formula (I), X is a hydrogen atom or a halogen atom; Y is a group represented by formula (II); R and n Contains a 2H-pyridazin-3-one derivative of formula (I) or a pharmaceutically suitable acid addition salt thereof, as defined in relation to formula (I).

  In this subgroup, a suitable pharmaceutical composition comprises, as an active ingredient, in formula (I), R represents a hydrogen atom or a methyl group, X represents a hydrogen atom or a chlorine atom, and Y and n are as defined above. Or a 2H-pyridazin-3-one derivative represented by the formula (I) or a pharmaceutically suitable acid addition salt thereof.

  A particularly suitable pharmaceutical composition is 4-chloro-5- {2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] ethylamino} as an active ingredient -2-methyl-2H-pyridazin-3-one, 4-chloro-5- {3- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] propylamino } -2-Methyl-2H-pyridazin-3-one, or a pharmaceutically suitable acid addition salt thereof.

  The invention also relates to the use of a compound of formula (I) or a pharmaceutically suitable acid addition salt thereof in the manufacture of a pharmaceutical composition having a neuroleptic action.

  Furthermore, the present invention provides a non-toxic amount of a 2H-pyridazin-3-one derivative represented by the formula (I) or a pharmaceutically suitable acid addition salt thereof for diseases associated with mental and emotional disorders, particularly schizophrenia. The present invention relates to a method of treatment administered to patients suffering from illness.

  The invention is further illustrated by the following examples.

4- {2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] ethylamino} -5-chloro-2-methyl-2H-pyridazin-3-one Preparation of
2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] ethylamine 1.5 g (5.7 mmol), dioxane 50 cm ³ , 4,5-dichloro-2 A mixture of 0.93 g (5.2 mmol) of methyl-2H-pyridazin-3-one and 1.38 g of potassium carbonate was boiled for 24 hours under stirring. The reaction mixture was then filtered and evaporated and the crude product was chromatographed on silica gel using a 3: 1 mixture of hexane and acetone as solvent. Fractions containing product were combined and evaporated and the residue was suspended in diethyl ether, filtered and dried.

  In this way 0.74 g (35.4%) of the title compound was obtained.

Melting point: 108-109 ° C
IR (KBr): 3290, 1630, 1607, 1554
¹ H-NMR (CDCl ₃ , i400): 7.76 (m, 1H), 7.50 (s, 1H), 7.24 (dd, J ₁ = 1.7 Hz, J ₂ = 8.5 Hz, 1H), 7.70 (˜dt, J _d = 1.8Hz, J _t = 8.8Hz, 1H), 6.47 (b, 1H), 3.91 (m, 2H), 3.73 (s, 3H), 3.08 (m, 3H), 2.72 (m, 2H), 2.31 (m, 2H), 2.03 (m, 4H)
¹³ C-NMR (CDCl ₃ , i400): 164.07 (d, J = 251.0 Hz), 163.81, 160.83, 156.37, 139.79, 139.07, 122.81, 117.15, 112.37 (d, J = 25.6 Hz), 97.38 (d, J = 26.7Hz), 57.44, 53.06, 40.53, 39.93, 34.34, 30.31

4- {3- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] propylamino} -5-chloro-2-methyl-2H-pyridazin-3-one Preparation of
4- (3-bromopropylamino) -5-chloro-2-methyl-2H-pyridazin-3-one 1.12 g (4 mmol), acetonitrile 20 cm ³ , 6-fluoro-3-piperidin-4-yl-1, A mixture of 1.05 g (4.8 mmol) of 2-benzisoxazole and 0.87 cm ³ of triethylamine was boiled for 2 hours under stirring. The reaction mixture was then evaporated and 30 cm ³ of water was added to the crude product. The aqueous phase was extracted 3 times using 30 cm ³ of ethyl acetate each time. The combined organic phases were washed twice using 30 cm ³ of water each time and dried over anhydrous magnesium sulfate. After filtration, the organic phase was evaporated and the resulting crude product was recrystallized from 2-propanol.

  In this way 1.1 g (65.8%) of the title product was obtained.

Melting point: 117-119 ° C
Elemental analysis for C ₂₀ H ₂₃ ClFN ₅ O ₂ (419.89):
Theoretical values: C 57.21%, H 5.52%, N 16.68%, Cl 8.44%
Measurements: C 56.94%, H 5.50%, N 16.57%, Cl 8.43%
IR (KBr): 3200, 1611, 1493
¹ H-NMR (CDCl ₃ , i400): 8.16 (bdd, J ₁ = 5.3 Hz, J ₂ = 8.3 Hz, 1 H), 7.47 (s, 1 H), 7.23 (m, 2 H), 7.04 (˜td, J _d = 2.1Hz, J _t = 8.9Hz, 1H), 3.92 (~ q, J = 6.1Hz, 2H), 3.75 (s, 3H), 3.14 (m, 3H), 2.58 (m, 2H), 2.34 ( m, 2H), 2.18 (m, 2H), 2.00 (m, 2H), 1.85 (m, 2H)
¹³ C-NMR (CDCl ₃ , i400): 164.11 (d, J = 250.6 Hz), 164.02 (d, J = 13.4 Hz), 161.23, 156.48, 139.92, 139.45, 123.70 (d, J = 10.7 Hz), 117.15 , 112.15 (d, J = 24.8Hz), 105.82, 97.21 (d, J = 26.7Hz), 57.28, 53.73, 44.06, 39.88, 34.73, 30.01, 26.49

Preparation of 4- {3- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] propylamino} -5-chloro-2H-pyridazin-3-one
4- (3-Bromopropylamino) -5-chloro-2H-pyridazin-3-one 4.32 g (16 mmol), acetone 80 cm ³ , 6-fluoro-3-piperidin-4-yl-1,2-benzoiso A mixture of 4.11 g (16.8 mmol) of oxazole, 4.48 g (32 mmol) of potassium carbonate and 0.27 g (1.6 mmol) of potassium iodide was boiled for 24 hours under stirring. The reaction mixture was then evaporated and the crude product was chromatographed on silica gel using a 1: 1: 0.2 mixture of hexane, ethyl acetate and methanol as solvent. Fractions containing product were combined and evaporated and the residue was suspended in diethyl ether, filtered and dried.

  There was thus obtained 1.94 g (30.0%) of the title compound.

Melting point: 198-200 ° C
Elemental analysis for C ₁₉ H ₂₁ ClFN ₅ O ₂ :
Theoretical values: C 56.23%, H 5.22%, N 17.26%, Cl 8.74%
Measurements: C 55.80%, H 5.17%, N 16.99%, Cl 8.52%
IR (KBr): 3348, 1615, 1494
¹ H-NMR (CDCl ₃ , i400): 12.82 (s, 1H), 8.22 (bdd, J ₁ = 5.6 Hz, J ₂ = 8.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.32 (m, 3H), 3.81 (m, 2H), 3.4 to 3.0 (m, 5H), 2.4 to 2.0 (m, 6H), 1.84 (m, 2H)
¹³ C-NMR (CDCl ₃ , i400): 166.05 (d, J = 250.3 Hz), 163.15 (d, J = 14.5 Hz), 161.22, 156.94, 140.03, 139.53, 124.05 (d, J = 11.1 Hz), 117.19 , 112.55 (d, J = 25.3Hz), 105.43, 97.20 (d, J = 27.5Hz), 56.06, 52.95, 42.74, 33.51, 29.53, 26.73

4-Chloro-5- {2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] ethylamino} -2-methyl-2H-pyridazin-3-one Preparation of
1.9 g (8.6 mmol) of 4-chloro-5- (2-chloroethylamino) -2-methyl-2H-pyridazin-3-one, 40 cm ^{3 of} acetonitrile, 6-fluoro-3-piperidin-4-yl A mixture of 2.07 g (9.4 mmol) of 1,2-benzisoxazole, 2.36 g (32 mmol) of potassium carbonate and 0.17 g (1.6 mmol) of potassium iodide was boiled for 24 hours under stirring. . The reaction mixture was then filtered through a carbon bed containing magnesium sulfate and the organic phase was evaporated. The crude product was dissolved in ethyl acetate, washed with water and the organic phase was dried over anhydrous magnesium sulfate. After filtration, the organic phase was evaporated and the resulting crude product was recrystallized from ethyl acetate.

  In this way 2.8 g (80.5%) of the title compound was obtained.

Melting point: 145-147 ° C
Elemental analysis for C ₁₉ H ₂₁ ClFN ₅ O ₂ (405.86):
Theoretical values: C 56.23%, H 5.22%, N 17.26%, Cl 8.74%
Measurements: C 55.73%, H 5.26%, N 16.98%, Cl 8.89%
IR (KBr): 3278, 1635, 1616
¹ H-NMR (CDCl ₃ , i400): 7.66 (dd, J ₁ = 5.1 Hz, J ₂ = 8.7 Hz, 1H), 7.56 (s, 1H), 7.25 (dd, J ₁ = 2.1 Hz, J ₂ = 8.5Hz, 1H), 7.07 (~ td, J _d = 2.1Hz, J _t = 8.8Hz, 1H), 5.62 (bt, 1H), 3.76 (s, 3H), 3.40 (~ q, J = 5.6Hz, 2H), 3.13 (m, 1H), 3.04 (m, 2H), 2.75 (t, J = 6.0Hz, 2H), 2.32 (m, 2H), 2.10 (m, 4H)
¹³ C-NMR (CDCl ₃ , i400): 164.03 (d, J = 250.6 Hz), 163.81 (d, J = 13.4 Hz), 160.71, 157.75, 144.04, 125.62, 122.35 (d, J = 11.1 Hz), 117.13 , 112.39 (d, J = 25.6Hz), 107.40, 97.40 (d, J = 27.1Hz), 56.02, 52.92, 40.11, 39.23, 34.20, 30.48

4-chloro-5- {3- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] propylamino} -2-methyl-2H-pyridazin-3-one Preparation of
2.4 g (10 mmol) of 4-chloro-5- (2-chloropropylamino) -2-methyl-2H-pyridazin-3-one, 40 cm ^{3 of} acetonitrile, 6-fluoro-3-piperidin-4-yl-1 , 2-Benzisoxazole 2.46 g (11 mmol), potassium carbonate 2.8 g and potassium iodide 0.18 g were boiled under stirring for 24 hours. The reaction mixture was then cooled to room temperature and filtered. The filtered material was suspended in 100 cm ³ of water with stirring and filtered again. The filtered crude product was recrystallized from acetonitrile.

  In this way 2.4 g (57.3%) of the title compound were obtained.

Melting point 200 ~ 202 ° C
Elemental analysis for C ₂₀ H ₂₃ ClFN ₅ O ₂ (419.89):
Theoretical values: C 57.21%, H 5.52%, N 16.68%, Cl 8.44%
Measurements: C 56.78%, H 5.48%, N 16.38%, Cl 8.44%
IR (KBr): 3348, 1606
¹ H-NMR (DMSO-d ₆ , i400): 8.00 (dd, J ₁ = 5.3 Hz, J ₂ = 8.7 Hz, ₁ H), 7.91 (s, 1 H), 7.68 (dd, J ₁ = 2.1 Hz, J ₂ = 9.1Hz, 1H), 7.28 (~ dtm, J _d = 2.1Hz, J _t = 9.0Hz, 1H), 6.94 (bt, J = 5.7Hz, 1H), 3.58 (s, 3H), 3.42 (~ q, J = 6.1Hz, 2H), 3.16 (m, 1H), 3.00 (m, 2H), 2.43 (t, J = 6.3Hz, 2H), 2.07 (m, 4H), 1.89 (m, 2H), 1.74 (~ qn, J = 6.4Hz, 2H)
¹³ C-NMR (DMSO-d ₆ , i400): 163.81 (d, J = 248.0 Hz), 163.15 (d, J = 14.1 Hz), 161.56, 156.92, 144.84, 126.58, 123.89 (d, J = 11.1 Hz) , 117.44, 112.65 (d, J = 25.2Hz), 104.34, 97.27 (d, J = 27.5Hz), 56.07, 53.18, 41.66, 39.59, 33.52, 30.20, 26.08

Preparation of 5- {2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] ethylamino} -2-methyl-2H-pyridazin-3-one
5- (2-chloroethylamino) -2-methyl-2H-pyridazin-3-one 3.67 g (16.4 mmol), acetonitrile 90 cm ³ , 6-fluoro-3-piperidin-4-yl-1,2-benzoiso A mixture of 4.05 g (18.4 mmol) oxazole, 6.84 g potassium carbonate and 0.37 g potassium iodide was boiled under stirring for 24 hours. The reaction mixture was then cooled to room temperature and filtered. 100 cm ³ of water was added to the filtered material and the aqueous phase was extracted 5 times using 50 cm ³ of dichloromethane each time. The combined organic phases were washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was suspended in diethyl ether and filtered. The resulting crude product was recrystallized from acetonitrile.

  In this way 3.4 g (55.9%) of the title compound was obtained.

Melting point: 200-202 ° C
Elemental analysis for C ₁₉ H ₂₂ FN ₅ O ₂ (371.42):
Theoretical values: C 61.44%, H 5.97%, N 18.86%
Measurements: C 62.00%, H 5.98%, N 18.84%
IR (KBr): 3261, 1620, 1571, 1114
_{^{1 H-NMR (CDCl 3,}} i400): 8.01 (dd, J 1 = 5.4Hz, J 2 = 8.6Hz, 1H), 7.68 (dd, J 1 = 2.1Hz, J 2 = 9.1Hz, 1H), 7.53 (s, 1H), 7.28 (dd, J ₁ = 2.1Hz, J ₂ = 8.5Hz, 1H), 6.80 (bt, J = 5.9Hz, 1H), 5.51 (s, 1H), 3.47 (s, 3H) , 3.16 (m, 1H), 3.15 (m, 2H), 3.01 (m, 2H), 2.52 (m, 2H), 2.19 (m, 2H), 2.05 (m, 2H), 1.84 (m, 2H)
¹³ C-NMR (DMSO-d ₆ , i400): 163.80 (d, J = 247.6 Hz), 163.16 (d, J = 14.1 Hz), 161.52, 161.03, 149.17, 131.01, 123.95 (d, J = 11.4 Hz) , 117.44, 112.65 (d, J = 25.2Hz), 97.50 (d, J = 27.5Hz), 94.40, 56.11, 53.16, 39.49, 38.29, 33.54, 30.22

Preparation of 5- {3- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] propylamino} -2-methyl-2H-pyridazin-3-one
4- (3-chloropropylamino) -2-methyl-2H-pyridazin-3-one hydrochloride 4.12 g (17.3 mmol), acetonitrile 100 cm ³ , 6-fluoro-3-piperidin-4-yl-1,2- A mixture of 4.29 g (19.5 mmol) of benzoisoxazole, 7.24 g of potassium carbonate and 0.39 g of potassium iodide was boiled for 24 hours under stirring. The reaction mixture was then cooled to room temperature and filtered. 150 cm ³ of water was added to the filtered material and the aqueous phase was extracted 5 times using 90 cm ³ of dichloromethane each time. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered through activated carbon. The organic phase was evaporated under reduced pressure and the resulting residue was suspended in diethyl ether and then filtered. The crude product was recrystallized from acetonitrile.

  In this way 4.14 g (62.2%) of the title compound were obtained.

Melting point: 163-165 ° C
Elemental analysis for C ₂₀ H ₂₄ FN ₅ O ₂ (385.44):
Theoretical values: C 62.32%, H 6.28%, N 18.17%
Measurements: C 62.18%, H 6.27%, N 18.09%
IR (KBr): 3264, 1624, 1591, 1119
¹ H-NMR (CDCl ₃ , i400): 7.71 (dd, J ₁ = 5.0 Hz, J ₂ = 8.7 Hz, ₁ H), 7.32 (s, 1 H), 7.26 (dd, J ₁ = 2.1 Hz, J ₂ = 8.4Hz, 1H), 7.10 (dt, J _d = 2.1Hz, J _t = 8.8Hz, 1H), 6.48 (b, 1H), 5.65 (d, J = 2.7Hz, 1H), 3.66 (s, 3H) , 3.22 (m, 5H), 2.72 (m, 2), 2.42 (m, 2H), 2.42 (m, 4H), 1.93 (m, 2H)
¹³ C-NMR (DMSO-d ₆ , i400): 164.26 (d, J = 251.8 Hz), 164.00 (d, J = 13.7 Hz), 162.23, 160.42, 148.81, 130.69, 122.29 (d, J = 11.1 Hz) , 117.22, 112.61 (d, J = 25.2Hz), 97.52 (d, J = 26.7Hz), 96.38, 57.21, 53.22, 42.31, 38.94, 33.70, 30.16, 23.92

Preparation of 5- {2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] ethylamino} -4-chloro-2H-pyridazin-3-one
5.6 g (22.2 mmol) of 5- (3-bromoethylamino) -4-chloro-2H-pyridazin-3-one, anhydrous dimethylformamide 16 cm ³ , 6-fluoro-3-piperidin-4-yl-1,2 A mixture of 5.62 g (25.5 mmol) of benzoisoxazole, 8.85 cm ^{3 of} triethylamine and 0.44 g of potassium iodide was stirred at 60 ° C. for 2 hours. The reaction mixture was then cooled to room temperature and a solution containing 5.46 g of sodium carbonate in 50 cm ^{3 of} water was added dropwise. The mixture was stirred for 30 minutes, the resulting suspension was filtered and the material separated by filtration was washed 3 times with 20 cm ³ of water each time. The resulting crude product was dissolved in a 9: 1 mixture of acetonitrile and water while boiling, filtered hot and the mother liquor was evaporated to 1/3 initial volume. The mother liquor was then cooled with ice and stirred for 2 hours. The obtained crystals were collected by filtration.

  In this way 6.75 g (77.6%) of the title compound was obtained.

Melting point: 229-231 ° C
Elemental analysis for C ₁₈ H ₁₉ ClFN ₅ O ₂ (391.84):
Theoretical values: C 55.18%, H 4.89%, Cl 9.05%, N 17.87%
Measurements: C 54.79%, H 4.94%, Cl 8.75%, N 17.56%
IR (KBr): 3305, 3141, 1641, 1607
¹ H-NMR (DMSO-d ₆ , i400): 12.58 (bs, 1H), 7.96 (dd, J ₁ = 5.3 Hz, J ₂ = 8.8 Hz, 1H), 7.88 (s, 1H), 7.68 (dd, J ₁ = 2.1Hz, J ₂ = 9.1Hz, 1H), 7.30 (~ td, J _d = 2.1Hz, J _t = 9.1Hz, 1H), 6.42 (bt, J = 5.9Hz, 1H), 3.47 (~ q, J = 6.1Hz, 2H), 3.15 (m, 1H), 3.01 (m, 2H), 2.57 (t, J = 6.2Hz, 2H), 2.23 (m, 2H), 2.02 (m, 2H), 1.80 (m, 2H)
¹³ C-NMR (DMSO-d ₆ , i400): 163.79 (d, J = 248.0 Hz), 163.18 (d, J = 14.1 Hz), 161.46, 157.98, 145.28, 128.09, 127.96, 123.90 (d, J = 11.0 Hz), 123.80 (d, J = 8.7Hz), 117.37 (d, J = 0.8Hz), 112.72 (d, J = 24.0Hz), 112.66 (d, J = 24.8Hz), 104.40, 97.61 (d, J = 27.1Hz), 97.45 (d, J = 27.5Hz), 57.23, 57.40, 53.12, 39.70, 33.54, 33.44, 30.40

Preparation of 5- {2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] ethylamino} -2H-pyridazin-3-one
5- (2-chloroethylamino) -2H-pyridazin-3-one hydrochloride 2.72 g (12.9 mmol), anhydrous dimethylformamide 11 cm ³ , 6-fluoro-3-piperidin-4-yl-1,2-benzoiso A mixture of 5.0 g (22.7 mmol) of oxazole, 6.3 cm ^{3 of} triethylamine and 0.21 g of potassium iodide was stirred at reflux temperature for 8 hours. The reaction mixture was then cooled to room temperature and filtered. A solution containing 2.6 g of sodium bicarbonate in 40 cm ^{3 of} water was added dropwise to the mother liquor. The resulting precipitate was collected by filtration, suspended in 100 ml of dichloromethane, stirred for 30 minutes, and filtered again. The resulting crude product was recrystallized from a 4: 1 mixture of water and acetonitrile. The formed crystals were collected by filtration.

  In this way 2.98 g (64.6%) of the title compound was obtained.

Melting point: 97-99 ° C
Elemental analysis for C ₁₈ H ₂₀ FN ₅ O ₂ (357.39):
Theoretical values: C 60.49%, H 5.64%, N 19.60%
Measurements: C 59.97%, H 5.74%, N 19.28%
IR (KBr): 3261, 1616, 1272, 1176
¹ H-NMR (DMSO-d ₆ , i400): 11.92 (bs, 1H), 8.00 (dd, J ₁ = 5.0 Hz, J ₂ = 8.8 Hz, 1H), 7.68 (dd, J ₁ = 2.2 Hz, J ₂ = 9.2Hz, 1H), 7.52 (d, J = 2.6Hz, 1H), 7.28 (td, J _d = 2.2Hz, J _t = 9.0Hz, 1H), 6.84 (bt, J = 5.2Hz, 1H) , 5.42 (d, J = 2.4Hz, 1H), 3.15 (m, 1H), 3.01 (m, 2H), 3.02 (m, 2H), 2.56 (t, J = 6.5Hz, 2H), 2.20 (m, 2H), 2.03 (m, 2H), 1.87 (m, 2H)
¹³ C-NMR (DMSO-d ₆ , i400): 163.80 (d, J = 248.0 Hz), 163.18 (d, J = 14.1 Hz), 162.34, 161.5, 149.43, 131.67, 123.93 (d, J = 11.4 Hz) , 117.42, 112.64 (d, J = 25.2Hz), 97.49 (d, J = 27.1Hz), 94.36, 56.10, 57.40, 53.16, 39.37, 33.56, 30.22

Claims (16)

Formula (I)

Wherein R is hydrogen or a C _1-4 alkyl group; X and Y are independently a hydrogen atom, a halogen atom or a formula (II)

(Where n is 1 or 2), provided that one of X and Y is always a group represented by the formula (II), and the other is hydrogen. 2H-pyridazin-3-one derivatives and pharmaceutically suitable acid addition salts thereof. The formula according to claim 1, wherein R is hydrogen or a C _1-4 alkyl group; X is hydrogen or halogen; Y is a group represented by formula (II); and n is 1 or 2. 2H-pyridazin-3-one derivatives represented by I) and pharmaceutically suitable acid addition salts thereof.   The compound according to claim 2, wherein R is a methyl group, X is chlorine, Y is a group represented by the formula (II), and n is 1 or 2, and a pharmaceutically suitable acid addition salt thereof. .   4-chloro-5- {2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] ethylamino} -2-methyl-2H-pyridazin-3-one And a pharmaceutically suitable acid addition salt thereof.   4-chloro-5- {3- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] propylamino} -2-methyl-2H-pyridazin-3-one And a pharmaceutically suitable acid addition salt thereof. The formula according to claim _1, wherein R is hydrogen or a C _1-4 alkyl group; X is a group represented by formula (II); Y is hydrogen or halogen; and n is 1 or 2. 2H-pyridazin-3-one derivatives represented by I) and pharmaceutically suitable acid addition salts thereof.   The 2H-pyridazin-3-one derivative according to claim 6, wherein R is hydrogen or a methyl group; X is a group represented by the formula (II); Y is chlorine; and n is 1 or 2. And pharmaceutically suitable acid addition salts thereof. A 2H- pyridazin -3- one derivative represented by formula (I) according to claim 1 , wherein Y is a group represented by formula (II) , and X, R and n are defined in claim 1. a method of manufacturing a certain 2H- pyridazin-3-one derivative or a pharmaceutically suitable acid addition salt as hereinbefore, the formula (III)

(Wherein Z is a leaving group; R, X and n are as defined above), an alkylaminopyridazin-3-one derivative represented by the formula (IV)

In reacted with represented by 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole; and optionally, the resulting 2H- pyridazin-3-one represented by the formula (I) A process for producing a 2H-pyridazin-3-one derivative or a pharmaceutically suitable acid addition salt thereof, characterized in that the derivative is converted into a pharmaceutically suitable acid addition salt or eliminated from the acid addition salt. The formula of claim 1 ( I ) Represented by 2H- Pyridazine -3- An on-derivative, wherein X is a formula (II) Wherein Y, R and n are as defined in claim 1 2H- Pyridazine -3- A method for producing an on-derivative or a pharmaceutically suitable acid addition salt thereof, comprising the formula ( V )

(Wherein Z is a leaving group; R, Y and n are as defined above) -3- On derivatives (IV)

Represented by 6- Fluoro -3- Piperidine -Four- Il -1,2- Reacting with benzisoxazole; and
If desired, the resulting formula ( I ) Represented by 2H- Pyridazine -3- Converting on-derivatives to or removal from their pharmaceutically suitable acid addition salts 2H- Pyridazine -3- A method for producing an on-derivative or a pharmaceutically suitable acid addition salt thereof. The formula of claim 1 ( I ) Represented by 2H- Pyridazine -3- An on-derivative, wherein X represents a hydrogen atom and Y represents a formula (II) Or Y represents a hydrogen atom, and X represents a formula (II) Wherein R and n are as defined in claim 1 2H- Pyridazine -3- A method for producing an on-derivative or a pharmaceutically suitable acid addition salt thereof, comprising the formula (VI)

(Where X ' And Y ' Represents a halogen atom; R is as defined above) -3- On derivatives (VII)

Wherein n is as defined above; and
If desired, the resulting formula ( I ) Represented by 2H- Pyridazine -3- Converting on-derivatives to or removal from their pharmaceutically suitable acid addition salts 2H- Pyridazine -3- Process for producing on derivatives and pharmaceutically suitable acid addition salts thereof. In addition to a common carrier, the formula of claim 1 ( I ) Wherein n, R, X and Y are as defined in claim 1. 2H- Pyridazine -3- A pharmaceutical composition comprising an ON derivative or a pharmaceutically suitable acid addition salt thereof. As an active ingredient, a 2H- pyridazin -3- one derivative represented by the formula ( I ) (wherein n, R, X and Y are as defined in claim 2) or a pharmaceutically suitable acid addition thereof 12. The pharmaceutical composition according to claim 11, comprising a salt . As an active ingredient, a 2H- pyridazin -3- one derivative represented by the formula ( I ) (wherein n, R, X and Y are as defined in claim 3) or a pharmaceutically suitable acid addition thereof 12. The pharmaceutical composition according to claim 11, comprising a salt . As an active ingredient, Four- Chloro -5- {2- [4- (6- Fluoro -1,2- Benzisoxazole -3- Il ) Piperidine -1- Il ] Ethylamino } -2- Methyl -2H- Pyridazine -3- 12. The pharmaceutical composition according to claim 11, comprising ON or a pharmaceutically suitable acid addition salt thereof. As an active ingredient, Four- Chloro -5- {3- [4- (6- Fluoro -1,2- Benzisoxazole -3- Il ) Piperidine -1- Il ] Propylamino } -2- Methyl -2H- Pyridazine -3- 12. The pharmaceutical composition according to claim 11, comprising ON or a pharmaceutically suitable acid addition salt thereof. A formula according to claim 1 in the manufacture of a pharmaceutical composition having a nerve blocking action. ( I ) Wherein n, R, X and Y are as defined in claim 1. 2H- Pyridazine -3- Use of an on derivative or a pharmaceutically suitable acid addition salt thereof.